olism is hydroxylation catalyzed by cytochrome p450 3a (cyp 3a). drugs which inhibit this metabolic pathway may have a profound effect on the clearance of triazolam (see contraindications and warnings for additional drugs of this type). triazolam is contraindicated with ketoconzaole, itraconazole, nefazodone, and several hiv protease inhibitors. drugs and other substances demonstrated to be cyp 3a inhibitors of possible clinical significance on the basis of clinical studies involving triazolam (caution is recommended during coadministration with triazolam) isoniazid coadministration of isoniazid increased the maximum plasma concentration of triazolam by 20%, decreased clearance by 42%, and increased half-life by 31%. oral contraceptives coadministration of oral contraceptives increased maximum plasma concentration by 6%, decreased clearance by 32%, and increased half-life by 16%. grapefruit juice coadministration of grapefruit juice increased the maximum plasma concentration of triazolam by 25%, increased the area under the concentration curve by 48%, and increased half-life by 18%. drugs demonstrated to be cyp 3a inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to triazolam or on the basis of in vitro studies with triazolam or other benzodiazepines (caution is recommended during coadministration with triazolam) available data from clinical studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: fluvoxamine, diltiazem, and verapamil. data from in vitro studies of triazolam suggest a possible drug interaction with triazolam for the following: sertraline and paroxetine. data from in vitro studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. caution is recommended during coadministration of any of these drugs with triazolam (see warnings ). drugs that affect triazolam pharmacokinetics by other mechanisms ranitidine coadministration of ranitidine increased the maximum plasma concentration of triazolam by 30%, increased the area under the concentration curve by 27%, and increased half-life by 3.3%. caution is recommended during coadministration with triazolam.

zolam, prescribe a lower initial dose of the opioid and titrate based upon clinical response. advise both patients and caregivers about the risks of respiratory depression and sedation when triazolam is used with opioids. advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see drug interactions ]. persistent or worsening insomnia because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. the failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. such findings have emerged during the course of treatment with sedative-hypnotic drugs. because some of the important adverse effects of sedative-hypnotics appear to be dose related (see precautions and dosage and administration ), it is important to use the smallest possible effective dose, especially in the elderly. "sleep-driving" and other complex behaviors complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. these events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. although behaviors such as sleep-driving may occur with sedative-hypnotics alone at therapeutic doses, the use of alcohol and other cns depressants with sedative-hypnotics appears to increase the risk of such behaviors, as does the use of sedative-hypnotics at doses exceeding the maximum recommended dose. due to the risk to the patient and the community, discontinuation of sedative-hypnotics should be strongly considered for patients who report a "sleep-driving" episode. other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. as with sleep-driving, patients usually do not remember these events. severe anaphylactic and anaphylactoid reactions rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including triazolam. some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. some patients have required medical therapy in the emergency department. if angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. patients who develop angioedema after treatment with triazolam should not be rechallenged with the drug. central nervous system manifestations an increase in daytime anxiety has been reported for triazolam after as few as 10 days of continuous use. in some patients this may be a manifestation of interdose withdrawal (see clinical pharmacology ). if increased daytime anxiety is observed during treatment, discontinuation of treatment may be advisable. a variety of abnormal thinking and behavior changes have been reported to occur in association with the use of benzodiazepine hypnotics including triazolam. some of these changes may be characterized by decreased inhibition, eg, aggressiveness and extroversion that seem excessive, similar to that seen with alcohol and other cns depressants (eg, sedative/hypnotics). other kinds of behavioral changes have also been reported, for example, bizarre behavior, agitation, hallucinations, depersonalization. in primarily depressed patients, the worsening of depression, including suicidal thinking, has been reported in association with the use of benzodiazepines. it can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation. because of its depressant cns effects, patients receiving triazolam should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle. for the same reason, patients should be cautioned about the concomitant ingestion of alcohol and other cns depressant drugs during treatment with triazolam tablets. as with some, but not all benzodiazepines, anterograde amnesia of varying severity and paradoxical reactions have been reported following therapeutic doses of triazolam. data from several sources suggest that anterograde amnesia may occur at a higher rate with triazolam than with other benzodiazepine hypnotics. triazolam interaction with drugs that inhibit metabolism via cytochrome p450 3a the initial step in triazolam metabolism is hydroxylation catalyzed by cytochrome p450 3a (cyp 3a). drugs that inhibit this metabolic pathway may have a profound effect on the clearance of triazolam. consequently, triazolam should be avoided in patients receiving very potent inhibitors of cyp 3a. with drugs inhibiting cyp 3a to a lesser but still significant degree, triazolam should be used only with caution and consideration of appropriate dosage reduction. for some drugs, an interaction with triazolam has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class. the following are examples of drugs known to inhibit the metabolism of triazolam and/or related benzodiazepines, presumably through inhibition of cyp 3a. potent cyp 3a inhibitors potent inhibitors of cyp 3a that should not be used concomitantly with triazolam include ketoconazole, itraconazole, nefazodone and several hiv protease inhibitors including ritonavir, indinavir, nelfinavir, saquinavir and lopinavir. although data concerning the effects of azole-type antifungal agents other than ketoconazole and itraconazole on triazolam metabolism are not available, they should be considered potent cyp 3a inhibitors, and their coadministration with triazolam is not recommended (see contraindications ). drugs demonstrated to be cyp 3a inhibitors on the basis of clinical studies involving triazolam (caution and consideration of dose reduction are recommended during coadministration with triazolam) macrolide antibiotics coadministration of erythromycin increased the maximum plasma concentration of triazolam by 46%, decreased clearance by 53%, and increased half-life by 35%; caution and consideration of appropriate triazolam dose reduction are recommended. similar caution should be observed during coadministration with clarithromycin and other macrolide antibiotics. cimetidine coadministration of cimetidine increased the maximum plasma concentration of triazolam by 51%, decreased clearance by 55%, and increased half-life by 68%; caution and consideration of appropriate triazolam dose reduction are recommended. other drugs possibly affecting triazolam metabolism other drugs possibly affecting triazolam metabolism by inhibition of cyp 3a are discussed in the precautions section (see precautions–drug interactions ).

ght. in some of these cases, insufficient time was allowed for the sleep period prior to awakening and before beginning activity. also, the concomitant use of alcohol may have been a factor in some cases. caution should be exercised if triazolam is prescribed to patients with signs or symptoms of depression that could be intensified by hypnotic drugs. suicidal tendencies may be present in such patients and protective measures may be required. intentional over-dosage is more common in these patients, and the least amount of drug that is feasible should be available to the patient at any one time. the usual precautions should be observed in patients with impaired renal or hepatic function, chronic pulmonary insufficiency, and sleep apnea. in patients with compromised respiratory function, respiratory depression and apnea have been reported infrequently.

ributions of drug and nondrug factors to the untoward event incidence rate in the population studied. even this use must be approached cautiously, as a drug may relieve a symptom in one patient while inducing it in others. (for example, an anticholinergic, anxiolytic drug may relieve dry mouth [a sign of anxiety] in some subjects but induce it [an untoward event] in others.) triazolam placebo number of patients 1003 997 % patients reporting: central nervous system drowsiness 14.0 6.4 headache 9.7 8.4 dizziness 7.8 3.1 nervousness 5.2 4.5 light-headedness 4.9 0.9 coordination disorders/ataxia 4.6 0.8 gastrointestinal nausea/vomiting 4.6 3.7 in addition to the relatively common (i.e., 1% or greater) untoward events enumerated above, the following adverse events have been reported less frequently (i.e., 0.9% to0.5%): euphoria, tachycardia, tiredness, confusional states/memory impairment, cramps/pain, depression, visual disturbances. rare (i.e., less than 0.5%) adverse reactions included constipation, taste alterations, diarrhea, dry mouth, dermatitis/allergy, dreaming/nightmares, insomnia, paresthesia, tinnitus, dysesthesia, weakness, congestion, death from hepatic failure in a patient also receiving diuretic drugs. in addition to these untoward events for which estimates of incidence are available, the following adverse events have been reported in association with the use of triazolam and other benzodiazepines: amnestic symptoms (anterograde amnesia with appropriate or inappropriate behavior), confusional states (disorientation, derealization, depersonalization, and/or clouding of consciousness), dystonia, anorexia, fatigue, sedation, slurred speech, jaundice, pruritus, dysarthria, changes in libido, menstrual irregularities, incontinence, and urinary retention. other factors may contribute to some of these reactions, eg, concomitant intake of alcohol or other drugs, sleep deprivation, an abnormal premorbid state, etc. other events reported include: paradoxical reactions such as stimulation, mania, an agitational state (restlessness, irritability, and excitation), increased muscle spasticity, sleep disturbances, hallucinations, delusions, aggressiveness, falling, somnambulism, syncope, inappropriate behavior and other adverse behavioral effects. should these occur, use of the drug should be discontinued. the following events have also been reported: chest pain, burning tongue/glossitis/stomatitis. laboratory analyses were performed on all patients participating in the clinical program for triazolam. the following incidences of abnormalities were observed in patients receiving triazolam and the corresponding placebo group. none of these changes were considered to be of physiological significance. triazolam placebo number of patients 380 361 % of patients reporting: low high low high hematology hematocrit less than 1% hemoglobin total wbc count 1.7 2.1 1.3 neutrophil count 1.5 1.5 3.3 1.0 lymphocyte count 2.3 4.0 3.1 3.8 monocyte count 3.6 4.4 1.5 eosinophil count 10.2 3.2 9.8 3.4 basophil count 1.7 2.1 1.8 urinalysis albumin — 1.1 — sugar — — rbc/hpf — 2.9 — 2.9 wbc/hpf — 11.7 — 7.9 blood chemistry creatinine 2.4 1.9 3.6 1.5 bilirubin 1.5 1.0 sgot 5.3 4.5 alkaline phosphatase 2.2 2.6 when treatment with triazolam is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are advisable. minor changes in eeg patterns, usually low-voltage fast activity, have been observed in patients during therapy with triazolam and are of no known significance.

olism is hydroxylation catalyzed by cytochrome p450 3a (cyp 3a). drugs which inhibit this metabolic pathway may have a profound effect on the clearance of triazolam (see contraindications and warnings for additional drugs of this type). triazolam is contraindicated with ketoconzaole, itraconazole, nefazodone, and several hiv protease inhibitors. drugs and other substances demonstrated to be cyp 3a inhibitors of possible clinical significance on the basis of clinical studies involving triazolam (caution is recommended during coadministration with triazolam) isoniazid coadministration of isoniazid increased the maximum plasma concentration of triazolam by 20%, decreased clearance by 42%, and increased half-life by 31%. oral contraceptives coadministration of oral contraceptives increased maximum plasma concentration by 6%, decreased clearance by 32%, and increased half-life by 16%. grapefruit juice coadministration of grapefruit juice increased the maximum plasma concentration of triazolam by 25%, increased the area under the concentration curve by 48%, and increased half-life by 18%. drugs demonstrated to be cyp 3a inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to triazolam or on the basis of in vitro studies with triazolam or other benzodiazepines (caution is recommended during coadministration with triazolam) available data from clinical studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: fluvoxamine, diltiazem, and verapamil. data from in vitro studies of triazolam suggest a possible drug interaction with triazolam for the following: sertraline and paroxetine. data from in vitro studies of benzodiazepines other than triazolam suggest a possible drug interaction with triazolam for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. caution is recommended during coadministration of any of these drugs with triazolam (see warnings ). drugs that affect triazolam pharmacokinetics by other mechanisms ranitidine coadministration of ranitidine increased the maximum plasma concentration of triazolam by 30%, increased the area under the concentration curve by 27%, and increased half-life by 3.3%. caution is recommended during coadministration with triazolam.

arfarin levels in male volunteers administered sodium warfarin orally. extremely high concentrations of triazolam do not displace bilirubin bound to human serum albumin in vitro . triazolam 14 c was administered orally to pregnant mice. drug-related material appeared uniformly distributed in the fetus with 14 c concentrations approximately the same as in the brain of the mother. in sleep laboratory studies, triazolam tablets significantly decreased sleep latency, increased the duration of sleep, and decreased the number of nocturnal awakenings. after 2 weeks of consecutive nightly administration, the drug's effect on total wake time is decreased, and the values recorded in the last third of the night approach baseline levels. on the first and/or second night after drug discontinuance (first or second post-drug night), total time asleep, percentage of time spent sleeping, and rapidity of falling asleep frequently were significantly less than on baseline (predrug) nights. this effect is often called "rebound" insomnia. the type and duration of hypnotic effects and the profile of unwanted effects during administration of benzodiazepine drugs may be influenced by the biologic half-life of administered drug and any active metabolites formed. when half-lives are long, the drug or metabolites may accumulate during periods of nightly administration and be associated with impairments of cognitive and motor performance during waking hours; the possibility of interaction with other psychoactive drugs or alcohol will be enhanced. in contrast, if half-lives are short, the drug and metabolites will be cleared before the next dose is ingested, and carry-over effects related to excessive sedation or cns depression should be minimal or absent. however, during nightly use for an extended period pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may develop. if the drug has a short half-life of elimination, it is possible that a relative deficiency of the drug or its active metabolites (ie, in relationship to the receptor site) may occur at some point in the interval between each night's use. this sequence of events may account for two clinical findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics: 1) increased wakefulness during the last third of the night and 2) the appearance of increased daytime anxiety after 10 days of continuous treatment. in a study of elderly (62–83 years old) versus younger subjects (21–41 years old) who received triazolam at the same dose levels (0.125 mg and 0.25 mg), the elderly experienced both greater sedation and impairment of psychomotor performance. these effects resulted largely from higher plasma concentrations of triazolam in the elderly.